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Background: Up to 60% of inflammatory bowel disease (IBD) patients treated with infliximab develop antibodies to infliximab (ATI), which are associated with low drug levels and loss of response (LOR). Hence, mapping out predictors of immunogenicity toward infliximab is essential for tailoring patient-specific therapy. Jewish Sephardi ethnicity, in addition to monotherapy, has been previously identified as a potential risk factor for ATI formation and infliximab failure., Objectives: To explore the association between Jewish sub-group ethnicity among patients with IBD and the risk of infliximab immunogenicity and therapy failure. To confirm findings of a previous cohort that addressed the same question., Methods: This retrospective cohort study included all infliximab-treated patients of Jewish ethnicity with regular prospective measurements of infliximab trough levels and ATI. Drug and ATI levels were prospectively measured, clinical data was retrieved from medical charts., Results: The study comprised 109 Jewish patients (54 Ashkenazi, 55 Sephardi) treated with infliximab. There was no statistically significant difference in proportion of ATI between Sephardi and Ashkenazi patients with IBD (32% Ashkenazi and 33% Sephardi patients developed ATI, odds ratio [OR] 0.944, P = 0.9). Of all variables explored, monotherapy and older age were the only factors associated with ATI formation (OR 0.336, 95% confidence interval 0.145-0.778, P = 0.01, median 34 vs. 28, interquartile range 28-48, 23-35 years, P = 0.02, respectively)., Conclusions: Contrary to previous findings, Sephardi Jewish ethnicity was not identified as a risk factor for ATI formation compared with Ashkenazi Jewish ethnicity. Other risk factors remained unchanged.

Background: Mucosal healing has been associated with long-term response to therapy for Crohn disease (CD). However, little is known about the significance of terminal ileum (TI) transmural thickness in predicting clinical outcomes., Methods: In this retrospective observational cohort study, we examined the association of an index ultrasonographic assessment of TI thickness during the maintenance phase and the subsequent clinical outcome of CD in a cohort of patients treated with infliximab (IFX). Treatment failure was defined as treatment discontinuation because of lack of efficacy, a need for dose escalation, or surgery. Clinical response was defined as treatment continuation in the absence of any of the aforementioned failure criteria., Results: Sixty patients with CD receiving IFX therapy were included in the study. The patients were followed for a median of 16 months (5-24 months) after an index intestinal ultrasound. Thirty-eight patients (63.3%) maintained response to the therapy and 22 patients (36.6%) failed the treatment, with a mean follow up of 10.5 months (6.5-17 months) vs 9.25 months (1-10.25 months), respectively. On univariate analysis, the only variables differing between treatment response and failure were a TI thickness of 2.8 vs 5 mm (P < 0.0001) and an IFX trough level of 6.6 vs 3.9 µg/mL (P = 0.008).On multivariable analysis, only a small bowel thickness of ≥4 mm was associated with the risk of treatment failure (odds ratio, 2.9; 95% CI, 1.49-5.55; P = 0.002)., Conclusions: Our findings suggest that transmural thickness of ≥4 mm can predict subsequent treatment failure in patients with CD treated using IFX, indicating transmural thickness <4 mm as a potential novel valuable therapeutic target., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Extra-intestinal manifestations (EIM) are common in inflammatory bowel diseases (IBD) and may affect up to 40% of the patients during the course of the disease. Peripheral arthralgia (PA) is by far the most common EIM. To date, TNFα inhibitors are the most established treatment for EIMs in IBD. Infliximab (IFX) trough levels (TL) and anti-IFX antibodies (ATI) are correlated with multiple outcomes in IBD such as clinical response and remission, mucosal healing, fistular healing, and more. So far, a correlation between PA and IFX TL\ATI has not been evaluated., Methods: This retrospective study included IBD patients followed by the gastroenterology department of Sheba Medical Center. Patients with active PA at onset of IFX treatment were included. IFX TL and ATI were evaluated at week 6, 14, and 26 and correlated with PA persistence., Results: Forty patients (37 Crohn's and 3 ulcerative colitis) with IBD-related PA were included. The overall prevalence of PA was 55% (22/40), 42.5% (17/40), and 55% (22/40) after 6, 14, and 26 weeks, respectively. IFX trough drug levels were not associated with reported PA at week 6 [median, 11.8 μg/ml (IQR 6.6-15.5) vs 10.05 μg/ml (IQR 7.35-12.87), p = 0.56], week 14 [median, 4.7 μg/ml (IQR 2.3-7) vs 3.1 μg/ml (IQR 1.35-7.35), p = 0.55], and week 26 [median, 3 μg/ml (IQR 1.15-5.17) vs 3.4 μg/ml (IQR 0.13-6.75), p = 0.94]. Detectable ATI were significantly more prevalent in patients with PA than in patients without PA at week 26 [11/22 (50%) vs 3/18 (16.7%), p = 0.028]., Conclusions: In patients with IBD-related PA, ATI are associated with an increased risk of persistence of PA. No direct correlation was demonstrated between IFX TL and persistence of PA.

Introduction: Loss of response (LOR) to infliximab occurs in ∼30% of IBD patients. At time of LOR, lower infliximab-trough-levels (TL), in the absence of anti-drug-antibodies (ATI), have been associated with the need for therapy escalation. Nevertheless, few studies have examined the outcome of infliximab-therapy intensification, based on different TL., Aim: To evaluate the impact of infliximab-TL on efficacy of therapy intensification (dose-elevation/interval-shortening)., Methods: This was a retrospective observational study performed at two tertiary-centers between 2013-2017. Study population included IBD patients who underwent infliximab therapy escalation (dose elevation/interval shortening) due to clinical LOR. Patients with TL < 3 μg/ml or positive ATI were excluded. TL and clinical scores before intensification and after 6, 12 months were obtained prospectively., Results: Forty-eight IBD patients were included; 23(49%), and 29(60%) reached clinical remission by 6, 12 months before intensification. TL among patients in clinical remission were significantly lower than among those clinically active, both at 6 (p = 0.001, median TL 4.7,8.7 μg/ml, IQR 3.6-8.1, 5.9-16 μg/ml) and 12 months (p = 0.005, median TL 4.6,8.7 μg/ml, IQR 3.6-8, 5.3-16 μg/ml), respectively., Conclusions: In IBD patients experiencing clinical LOR to infliximab in the absence of ATI, success of doubling the dose was inversely associated with baseline TL. Patients with baseline TL above 9 mcg/ml were very unlikely to reach clinical remission., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Direct head-to-head studies comparing the long-term outcomes of infliximab (IFX) to adalimumab (ADA) in Crohn's disease (CD) are sparse., Aims: We compared the short-term and long-term efficacy and safety of IFX and ADA in CD., Methods: We performed a single-center retrospective study including biologic-naïve adult patients with CD who were started on IFX or ADA at the McGill University Health Center. The primary end points were clinical response and remission at 12 months. Secondary end points included corticosteroid-free remission at 12 months, durable remission, and treatment failure with need for steroids, hospitalization or surgery. Safety was also assessed., Results: Two hundred and twenty patients were included (143 IFX, 77 ADA). Patients on IFX had a higher prevalence of fistulizing or perianal disease and corticosteroid treatment at baseline. Rates of clinical remission and corticosteroid-free remission at 12 months were similar between both groups: 63.8 versus 76.3% (p = 0.139) and 54.1 versus 44.7% (p = 0.354), respectively, for IFX and ADA. Combination therapy led to significantly higher remission rates at 12 months compared to monotherapy for patients on IFX (81.2 vs. 52.1%, p = 0.008), but not for those on ADA. Higher rates of adverse events were reported with IFX compared to ADA (p = 0.006)., Conclusions: Our real-life experience in biologic-naïve CD patients demonstrated that patients started on IFX were more likely to have a harder-to-treat phenotype. Despite that, efficacy end points were similar between both groups. Clinical remission was higher in patients with combination therapy for IFX, but not for those on ADA. This warrants further investigation.

Background: Endoscopic recurrence is associated with a risk of clinical recurrence in patients with Crohn's disease after ileocecal or small bowel resection. Drug levels and presence of antidrug antibodies are associated with important clinical and endoscopic outcomes in patients with Crohn's disease treated with tumor necrosis factor inhibitors, such association was not evaluated for endoscopic postsurgical recurrence., Methods: Consecutive patients with Crohn's disease treated with anti-tumor necrosis factors after surgery were identified in the databases of the participating centers. Anti-tumor necrosis factor levels and antidrug antibodies were correlated with Rutgeerts score on colonoscopy performed ≥6 months postoperatively. Significant endoscopic recurrence (SER) was defined as Rutgeerts score >2., Results: Seventy-three consecutive patients (32-infliximab, 41-adalimumab) were included in the study. The colonoscopies were performed after a median of 15 (7-43) months after surgery and 8 (6-15) months from treatment onset. SER was demonstrated in 26/73 (35.6%) of the patients. The need for dose optimization, as well as trough infliximab levels (2.4 μg/mL [0.45-4.1] versus 1.1 (0-0.6), P = 0.008) and presence of antidrug antibodies (1/18 [5.6%] versus 10/14 [71.4%], P = 0.0001) were significantly associated with a risk of SER. The optimal cutoff infliximab level for prediction of SER was 1.8 μg/mL. No association between adalimumab levels and antiadalimumab antibodies was demonstrated.

Background: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA])., Methods: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months., Results: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy., Conclusions: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.

Background: The association of infliximab [IFX] trough levels with clinical and endoscopic outcomes in inflammatory bowel disease is well established. However, there is scarce data regarding the association of perianal fistula response with IFX. The aim of this study was to establish whether early induction infliximab levels and anti-infliximab antibodies [ATIs] are associated with perianal fistula response., Methods: Consecutive CD patients with perianal fistulae that were treated with IFX between 2008 and 2016 were included in the study. Response was defined as cessation or significant improvement of fistula drainage. Patients with unavailable IFX level or ATI measurements and/or missing clinical follow-up at Week 14 were excluded., Results: A total of 36 patients with perianal fistulae were included; 25/36 [69.4%] responded to treatment by Week 14. The median induction IFX levels at Weeks 2, 6 and 14 in the responders group at Week 14 were higher compared with those of the non-responders group [20/5.6 µg/mL, P = 0.0001; 13.3/2.55 µg/mL P = 0.0001; 4.1/0.14 µg/mL, P = 0.01]. On multivariate analysis, IFX leve at Weeks 2 and 6 were significantly associated with fistula response at Weeks 14 and 30. IFX drug levels of 9.25 µg/mL at Week 2 and 7.25 µg/mL at Week 6 were the best predictors of fistula response., Conclusion: High IFX trough levels during induction are associated with favorable fistula response to anti-TNF treatment. If validated in a larger prospective study, our findings may help guide anti-TNF treatment in patients with perianal CD, and suggest serum level-guided treatment escalation in non-responders or prompt changing of biologic treatment in non-responders., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background & Aims: Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission., Methods: We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods., Results: In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88-6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02-6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events., Conclusions: In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance., Methods: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera., Results: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P = 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 μg/mL, respectively P = 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P = 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P = 0.028)., Conclusions: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease.

Background & Aims: It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels., Methods: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein., Results: Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 μg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 μg/mL, P = .01). Levels of infliximab above 5 μg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 μg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 μg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 μg/mL. In patients with measurable levels of infliximab >3 μg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003)., Conclusions: In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Higher infliximab trough levels (TLs) correlate with better clinical, inflammatory, and endoscopic outcomes among inflammatory bowel disease (IBD) patients. Although standard scheduled infliximab therapy regimen consists of infusions at pre-defined time-points (weeks 0, 2, 6, and every 8 weeks), short-period deviations from therapeutic schedule are common in 'real life', but the pharmacokinetic impact of these deviations has not been explored. In this study, we aim to determine whether short-period deviations from infusion schedule affect infliximab-TL. Methods: A retrospective analysis of all IBD patients receiving infliximab maintenance therapy every 8 weeks was conducted in a tertiary medical center. Patients with anti-drug antibodies, deliberate interval shortening and <3 sequential maintenance sera available were excluded. Associations between time since last infusion and TL were studied. Statistical analysis was performed using generalized estimating equations. Results: Out of over 10,000 sera, 2088 sera of 302 maintenance period stable infliximab-therapy-patients met inclusion criteria (median TL 4.1 μg/mL, interquartile range (IQR) 2.3–6.5 μg/mL). A delay beyond 3 days in infusion schedule (n > 59 days since last infusion) was found to significantly affect TL (mean difference in TL 0.9 μg/mL, 95% confidence interval (CI): 0.03–1.9 μg/mL, p < 0.04). Furthermore, among patients with delayed infusions, 80% had TL below 5 μg/mL, in comparison to 55% of patients who were not late (odds ratio (OR): 2.81, CI: 2.02–3.92, p < 0.0001). Conclusion: Real-life delays of ⩽3 days from infusion protocol can probably be allowed. Delays >3 days culminate in measurable decrease of TL, although effect on clinical outcome is unclear. This needs to be taken into account when interpreting drug-level test results. Summary: A total of 2088 sera of 302 maintenance period inflammatory bowel disease (IBD) patients treated with infliximab were analyzed, to assess effect of small deviations from infusion schedule on TLs. A significant decline in patients' trough level (TL) was noted as early as 3 days after scheduled infusion. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the risk of immunogenicity in patients with inflammatory bowel disease (IBD) who switched anti-tumor necrosis factor alpha (anti-TNFα) therapies to a subsequent anti-TNFα (either infliximab or adalimumab) is conflicting. We aimed to assess the risk of consecutive immunogenicity to anti-TNFα in a large cohort of patients. Methods: This was a multicenter retrospective study. Medical records of adult and pediatric IBD switchers who had pharmacokinetic data for both agents between 2014 and 2020 were retrieved. Data including age, sex, disease type, duration of therapies, and concomitant use of immunomodulators (IMMs) were recorded. Results: Overall, 164 patients were included [52% female; 88% Crohn's disease; mean age = 24.4 ± 14.6 years; 108 (66%) switched from infliximab to adalimumab and 56 (34%) vice versa]; 120 (73.1%) patients switched due to an immunogenic failure. Among patients switching therapy from infliximab to adalimumab due to an immunogenic failure immunogenicity to infliximab was significantly associated with consecutive immunogenicity to adalimumab (p = 0.026). Forthy four out of 120 patients (36.6%) with an immunogenic failure to the first anti-TNFα started an IMM with the second anti-TNFα. This combination with IMM was not associated with reduction of consecutive immunogenicity (p = 0.31), but it was associated with longer drug retention (p = 0.007). Multivariate analysis demonstrated that older age at second anti-TNFα, adjusted to the chronology of therapy and sex, was associated with increased immunogenicity to the second anti-TNFα. Conclusion: Patients with IBD who switch from infliximab to adalimumab following an immunogenic failure are at increased risk for consecutive immunogenicity to adalimumab. IMM use after a switch prolongs drug retention. [ABSTRACT FROM AUTHOR]

Summary: Background: Treatment paradigms for Crohn′s disease with perianal fistulae (CD‐pAF) are evolving. Aims: To study the impact of multimodality treatment in CD‐pAF on recurrence rates and the need for re‐interventions and to identify predictive factors for these outcomes. Methods: This was a multinational multicentre retrospective cohort study. Multimodality approach was defined as using a combination of medical treatments (anti‐TNFs ± immunomodulators ± antibiotics) along with surgical approach (examination under anaesthesia (EUA) ± seton drainage) at diagnosis of CD‐pAF. Univariable and multivariable analyses were performed for variables indicative of the need for reintervention. Results: A total of 253 patients were included. 65% of patients received multimodality approach. Multimodality treatment resulted in complete fistula healing in 52% of patients. Re‐intervention was needed in 27% of patients with simple and in 40.3% of those with complex fistula. On multivariable analysis multimodality treatment (OR: 0.35, 95% CI: 0.17‐0.57, P = 0.001), seton removal (OR: 0.090, 95% CI: 0.027‐0.30, P = 0.0001, therapy with infliximab (OR: 0.19, 95% CI: 0.06‐0.64, P = 0.007), and therapy with adalimumab (OR: 0.12, "95% CI: 0.026‐0.56, P = 0.007) were predictive of avoiding repeat surgery. Proctitis (OR: 3.76, 95% CI: 1.09‐12.96, P = 0.03) was predictive of the need for radical surgery (proctectomy, diverting stoma) while multimodality treatment reduced the need for radical surgery (OR: 0.21, 95% CI: 0.05‐0.81, P = 0.02). Conclusions: Multimodality treatment, anti‐TNFs use, and removal of setons after multimodality treatment can result in improved outcomes in CD patients with perianal fistulae and reduce the need for repeat surgery and radical surgery. [ABSTRACT FROM AUTHOR]

Objective To characterise the temporal evolution of antibodies to infliximab (ATI). Design Prospective observational study of infliximabtreated patients with inflammatory bowel disease between 2009 and 2012. Interventions Trough levels of infliximab and ATI were measured before each infusion by anti-X ELISA. Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation. The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately. Results 125 patients were included (98 Crohn's disease, 27 ulcerative colitis, median follow-up 11.5 ±22 months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier analysis showed that 42% of patients remained ATI-free by 4 years of treatment. Most (90%) of the patients who developed ATI did so within the first 12 months of therapy, whereas transient ATI were detected throughout the duration of infliximab therapy (p<0.001). ATI incidence was similar between patients who received infliximab previously (episodic/ interrupted therapy patients, n=14) and scheduledtherapy patients (n=111). In the scheduled group, combination immunomodulator+infliximab resulted in longer ATI-free survival compared with monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was enjoyed by 51% of patients, and serial measurements showed that ATI development often preceded the onset of clinical flare. Conclusions When followed prospectively, most patients who develop ATI do so within the first 12 months of therapy. This incidence is reduced by concomitant immunomodulator even in scheduledtherapy patients. In contrast, transient ATI, which are of little clinical significance, can appear haphazardly at any time during treatment. The onset of clinical loss of response may lag behind the appearance of antiinfliximab antibodies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Subjects maintained on infliximab scheduled therapy for inflammatory bowel disease may require dose optimization due to secondary loss of response. There are limited data on infliximab dose optimization for ulcerative colitis. Aims: To investigate dose optimization in ulcerative colitis patients with secondary loss of response. Methods: This was a retrospective multicentre study. Primary outcome was rapid clinical response assessed at the next administration of infliximab after dose intensification. Secondary outcomes were rapid clinical remission, and clinical response, remission and colectomy rate by week 52. Doubling the dose (10mg/kg q8 weeks) vs. shortening the dose interval (5mg/kg every 6 or 4 weeks) were compared. Results: Forty-one patients from eight centres were enrolled (15 for double dose and 26 for interval shortening). Rapid response was achieved in 37/41 patients (90.2%), while 19/41 (46.3%) achieved rapid clinical remission. At week 52, 28/41 patients were maintained in clinical remission, but 4 (9.8%) underwent colectomy. No difference was found between the two optimization strategies. Subjects achieving rapid clinical response had a significantly higher colectomy-free rate at week 52 (p =0.002). Conclusion: Dose optimization of infliximab was effective to restore clinical response or remission and to prevent colectomy in ulcerative colitis patients with secondary loss of response. [Copyright &y& Elsevier]

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay–based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Limited data suggest the absence of infliximab in breast milk, thereby implying the safety of this drug during breast-feeding. We aimed to re-evaluate the presence of infliximab in breast milk of nursing IBD patients. Methods: Serum and breast milk were obtained post-partum from 3 breast-feeding patients with Crohn''s disease before and after re-initiation of infliximab. ELISA assay was employed to measure infliximab level in maternal serum and in breast milk. The level of infliximab was also measured in breast milk of a control group of 8 nursing healthy mothers. Results: Infliximab was undetectable in breast milk prior to the first infusion and was also not measurable in 8 lactating women not exposed to infliximab. Infliximab levels in breast milk rose up to 101ng/ml within 2–3days of the infusion. These levels of infliximab in breast milk were roughly 1/200th of the level in blood. Conclusions: In contrast with prior reports, infliximab can be detected in the breast milk of nursing mothers. The miniscule amounts of infliximab transferred in breast milk are unlikely to result in systemic immune-suppression of the infant. Nonetheless, local effects of this exposure on the neonates'' intestine and potential immune sensitization or tolerization towards the drug can not be excluded and merit further investigations. [Copyright &y& Elsevier]

Infliximab and vedolizumab are effective treatments for inflammatory bowel disease (IBD), although associated with adverse events (AE). While low or non-existent drug levels and positive antidrug antibodies have been associated with therapeutic failure, there is no clear association between higher drug levels and AE. A cross-sectional study consisting of Crohn's disease (CD) and ulcerative colitis (UC) patients receiving infliximab or vedolizumab at the Sheba Medical Center was performed. Patients completed a questionnaire regarding AEs related to biological therapy. Serum trough levels obtained on the same day were analyzed. Objective measures of outcomes were retrieved from medical records. Questionnaires were completed by infliximab (n = 169) and vedolizumab (n = 88)-treated therapy patients. Higher infliximab levels were only numerically associated with the occurrence of at least one AE (p = 0.08). When excluding fatigue and abdominal pain, higher infliximab levels were statistically associated with the occurrence of at least one AE (p = 0.03). Vedolizumab drug levels > 18 μg/mL were also linked with the occurrence of more AEs. No specific association was observed between the increased levels of either infliximab or vedolizumab and specific AEs (neurological symptoms, upper GI symptoms, infectious complications, and musculoskeletal symptoms). As significant AEs are very rare, additional multi-center studies are required. [ABSTRACT FROM AUTHOR]